This is a Shannon award providing partial support for the research projects that fall short of the assigned Institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. DESCRIPTION (Adapted from the Applicant's Abstract): Osteoporosis is a bone wasting disease that causes considerable morbidity and afflicts 20 million Americans. Osteoporotic fractures occur when bone density falls below the fracture threshold, a change dependent upon peak bone density achieved by adulthood and net bone loss rate after menopause. There is a wide range of peak bone densities within the normal population, and 70% of this variability is inheritable. The investigators were unable to confirm the reported role of VDR alleles as a genetic determinant of bone density in their Southern California Caucasian female population, or in a Swiss population. Recognizing the importance of identifying the responsible genes and realizing that the RFLP approach in humans may not provide a feasible evaluation of the genes involved, studies were initiated in genetically-defined inbred strains of mice. The investigators have: 1) developed a genetic model consisting of two inbred strains, C57BL/6J and C3H/HeJ, in which there is a 50% difference in femoral bone density as measured by computerized tomography; 2) shown that the difference in femoral bone density is due to a decrease in the medullary cavity area and thus, an increase in cortical thickness in the C3H/HeJ compared with the C57BL/6J mice; and 3) shown that the bone resorption rate as measured by urine pyridinoline/creatinine is lower in the mice with the higher bone density. Based on this preliminary data, two hypotheses are advanced: 1) the difference in femoral bone density is determined by a fixed number of genes that can be mapped; and 2) the difference in femoral cortical bone density between the C57BL/6J and the C3H/HeJ mice is a consequence of specific gene effects on cellular mechanisms mediating endosteal bone resorption. To map genes, the investigators will apply 3 genetic approaches: 1) recombinant inbred (RI) strain analyses using the BXH RI strain set derived from C57BL/6J and C3H/HeJ progenitors; 2) intercross F2 progeny for quantitative trait loci-analyses (QTL) with the C57BL/6J and C3H/HeJ strains; and 3) recombinant congenic (RC) strains. Combining these approaches will reveal major and important modifying genes regulating bone density. To identify cellular mechanisms, the investigators will measure serum and urine bone formation and resorption markers as a function of age from weaning to 1 year, and also measure, by morphometric and cytochemical techniques, endosteal bone formation and bone resorption rates over the same time period. If they find that the osteoclast number is lower, they will quantitate the percentage of osteoclasts undergoing apoptosis to determine if the lower osteoclast number in the C3H/HeJ mice is due to increased apoptosis of osteoclasts. They propose to thoroughly characterize the cellular process(es), that determines the differential bone density so that they can match this process to the candidate gene(s) determined by genetic analyses. If the identified gene does not correspond to the difference in cell process(es) they will further evaluate the chromosomal location in search of an alternative gene. In future work, the investigators will test the cause and effect relationship between identified gene(s) and the cell process with either a knockout experiment, or by administering the gene product under question.